I cover cardiology news for CardioExchange, a social media website for cardiologists published by the New England Journal of Medicine. I was the editor of TheHeart.Org from its inception in 1999 until December 2008. Following the purchase of TheHeart.Org by WebMD in 2005, I became the editorial director of WebMD professional news, encompassing TheHeart.Org and Medscape Medical News. Prior to joining TheHeart.Org, I was a freelance medical journalist and wrote for a wide variety of medical and computer publications. In 1994-1995 I was a Knight Science Journalism Fellow at MIT. I have a PhD in English from SUNY Buffalo, and I drove a taxicab in New York City before embarking on a career in medical journalism. You can follow me on Twitter at: @cardiobrief.

A New Novartis Heart Failure Drug Might Be A Blockbuster

I try to avoid using words like “blockbuster” and “breakthrough” when writing about new drugs and treatments. I’ve been disappointed too many times. But, though they’ve been in short supply lately in cardiovascular medicine, sometimes there really are breakthroughs and blockbusters. In my career writing about cardiovascular medicine I’ve seen the introduction of the ACE inhibitors, statins, stents, ICDs, and clopidogrel, among others. All of these became multibillion-dollar products and, more importantly, vastly improved the prospects for millions of people with cardiovascular disease. Now there’s a new candidate that just might join this group. I’ll tell you why, but I can’t emphasize strongly enough that right now we only have extremely preliminary information. So be warned. And don’t be completely surprised if it does bomb out. We’ve been down this road before.

As I reported previously (here and here), early on Monday Novartis disclosed that the PARADIGM-HF trial testing LCZ696, a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), had been stopped early. As I later found out, the news was even better than Novartis had said in its press release. I spoke with the co-principal investigator of the trial, Milton Packer, who told me that the trial had been stopped because of a highly statistically significant reduction in cardiovascular mortality in patients taking LCZ696 instead of the current gold standard of treatment, an ACE inhibitor. Marc Pfeffer, a cardiologist at the Brigham and Women’s Hospital with long experience in heart failure, told me that he interprets “the stopping of a major clinical outcome trial for effectiveness by an experienced DSMB [Data and Safety Monitoring Board] as indicating that the final results will be both definitive and important.”

The first thing to know is that a reduction in cardiovascular mortality is a really big deal. In heart failure, and in other cardiovascular conditions, there are only a few therapies that have been able to show this benefit (such as, for example, an ACE inhibitor in heart failure or a statin in coronary disease). And the presence of these established therapies makes it even harder to find new drugs with added benefit. And, as best I can recall, there’s never been a case in which another drug has been shown to be dramatically superior to one of these bedrocks of therapy. In other words, if the PARADIGM-HF trial lives up to its promise, it may lead to LCZ696 replacing the ACE inhibitors and ARBs as a cornerstone of therapy. That would be huge.

“Better is what we need”

I spoke with Clyde Yancy, a leading heart failure expert and a former president of the American Heart Association. (Yancy told me he has no financial relationship with Novartis.) I should caution that he has no inside knowledge about this drug or this trial, but he is a knowledgeable observer of the heart failure scene. He was enthusiastic:

Potentially this is of incredible importance and could really be the breakthrough moment we’ve been seeking for some time. There has been an ongoing question of whether or not we could ever challenge the primacy of ACE inhibitor therapy in heart failure.

The key here, if it holds up of course, is that the drug might offer an advance over existing therapies. The AHA estimates that 5 million people in the US now have heart failure, and as the elderly population grows and more and more people survive after having a heart attack, this number is going to continue to grow rapidly. Said Yancy:

As good as ACE inhibitors have been in heart failure perhaps there is something that is better, and better is what we need. We won’t be able to fully arbitrate these results until they’re seen, but given the increasing morbidity of heart failure, the increasing cost of care, and the increasing cost to human life, having something better than an ACE inhibitor really does qualify as a breakthrough.

Yancy noted that there have been numerous incremental advances in the past– beta blockesr, aldosterone antagonists– that can be added to an ACE inhibitor or an ARB, but this study challenged the primacy of the ACE inhibitors. “This is as good an endpoint as you can get.”

Yancy said there were many questions that would still need to be asked. He will want to see how well the patients were treated in the trial, whether there is consistency across the subgroups, and, of course, what the drug will cost. One big advantage for ACE inhibitors and ARBs is that they’ve been around for a long enough time that they are available as inexpensive generics. To convince people and payers to spend more will require conclusive evidence of added benefit. And then there’s the novel problem of figuring out how to subtract a proven therapy from standard practice. That’s almost never been done before.

Finally, one additional word of caution. I mentioned above that we’ve been down this path before. Some of us remember the story of omapatrilat, a close chemical cousin to LCZ696. While under development by Bristol Myers it was also the subject of much hype and speculation. And then it crashed and burned, spectacularly, when it was found to induce angioedema. So far it appears there have been no signs of angioedema with LCZ696– and you can be sure they’ve looked closely for this– but omapatrilat is a great lesson demonstrating that there’s no such thing as a sure thing.

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